tbuckley/cabot-search huggingface dataset:
Bidirectional Movement of Emerging H5N8 Avian Influenza Viruses Between Europe and Asia via Migratory Birds Since Early 2020
Authors: Guogang Zhang, Bingying Li, Jayna Raghwani, Bram Vrancken, Ru Jia, Sarah C Hill, Guillaume Fournié, Yanchao Cheng, Qiqi Yang, Yuxin Wang, Zengmiao Wang, Lu Dong, Oliver G Pybus, Huaiyu Tian
Journal: Molecular Biology and Evolution (2023)

Abstract Migratory birds play a critical role in the rapid spread of highly pathogenic avian influenza (HPAI) H5N8 virus clade 2.3.4.4 across Eurasia. Elucidating the timing and pattern of virus transmission is essential therefore for understanding the spatial dissemination of these viruses. In this study, we surveyed &amp;gt;27,000 wild birds in China, tracked the year-round migration patterns of 20 bird species across China since 2006, and generated new HPAI H5N8 virus genomic data. Using this new data set, we investigated the seasonal transmission dynamics of HPAI H5N8 viruses across Eurasia. We found that introductions of HPAI H5N8 viruses to different Eurasian regions were associated with the seasonal migration of wild birds. Moreover, we report a backflow of HPAI H5N8 virus lineages from Europe to Asia, suggesting that Europe acts as both a source and a sink in the global HPAI virus transmission network.
Mapping Multi-Factor-Mediated Chromatin Interactions to Assess Dysregulation of Lung Cancer-Related Genes
Authors: Yan Zhang, Jingwen Zhang, Wei Zhang, Mohan Wang, Shuangqi Wang, Yao Xu, Lun Zhao, Xingwang Li, Guoliang Li
Journal: Genomics Proteomics & Bioinformatics (2023)

Abstract Studies on the lung cancer genome are indispensable for developing a cure for lung cancer. Whole-genome resequencing, genome-wide association studies, and transcriptome sequencing have greatly improved our understanding of the cancer genome. However, dysregulation of long-range chromatin interactions in lung cancer remains poorly described. To better understand the three-dimensional (3D) genomic interaction features of the lung cancer genome, we used the A549 cell line as a model system and generated high-resolution chromatin interactions associated with RNA polymerase II (RNAPII), CCCTC-binding factor (CTCF), enhancer of zeste homolog 2 (EZH2), and histone 3 lysine 27 trimethylation (H3K27me3) using long-read chromatin interaction analysis by paired-end tag sequencing (ChIA-PET). Analysis showed that EZH2/H3K27me3-mediated interactions further repressed target genes, either through loops or domains, and their distributions along the genome were distinct from and complementary to those associated with RNAPII. Cancer-related genes were highly enriched with chromatin interactions, and chromatin interactions specific to the A549 cell line were associated with oncogenes and tumor suppressor genes, such as additional repressive interactions on FOXO4 and promoter–promoter interactions between NF1 and RNF135. Knockout of an anchor associated with chromatin interactions reversed the dysregulation of cancer-related genes, suggesting that chromatin interactions are essential for proper expression of lung cancer-related genes. These findings demonstrate the 3D landscape and gene regulatory relationships of the lung cancer genome.
Global hypomethylation in childhood asthma identified by genome‐wide DNA‐methylation sequencing preferentially affects enhancer regions
Authors: Loreen Thürmann, Matthias Klös, Sebastian D. Mackowiak, Matthias Bieg, Tobias Bauer, Naveed Ishaque, Marey Messingschlager, Carl Herrmann, Stefan Röder, Mario Bauer, Sascha Schäuble, Erik Faessler, Udo Hahn, Dieter Weichenhan, Oliver Mücke, Christoph Plass, Michael Borte, Erika von Mutius, Gabriele I. Stangl, Roger Lauener, Anne M. Karvonen, Amandine Divaret‐Chauveau, Josef Riedler, Joachim Heinrich, Marie Standl, Andrea von Berg, Beate Schaaf, Gunda Herberth, Michael Kabesch, Roland Eils, Saskia Trump, Irina Lehmann
Journal: Allergy (2023)

Childhood asthma is a result of a complex interaction of genetic and environmental components causing epigenetic and immune dysregulation, airway inflammation and impaired lung function. Although different microarray based EWAS studies have been conducted, the impact of epigenetic regulation in asthma development is still widely unknown. We have therefore applied unbiased whole genome bisulfite sequencing (WGBS) to characterize global DNA-methylation profiles of asthmatic children compared to healthy controls.Peripheral blood samples of 40 asthmatic and 42 control children aged 5-15 years from three birth cohorts were sequenced together with paired cord blood samples. Identified differentially methylated regions (DMRs) were categorized in genotype-associated, cell-type-dependent, or prenatally primed. Network analysis and subsequent natural language processing of DMR-associated genes was complemented by targeted analysis of functional translation of epigenetic regulation on the transcriptional and protein level.In total, 158 DMRs were identified in asthmatic children compared to controls of which 37% were related to the eosinophil content. A global hypomethylation was identified affecting predominantly enhancer regions and regulating key immune genes such as IL4, IL5RA, and EPX. These DMRs were confirmed in n = 267 samples and could be linked to aberrant gene expression. Out of the 158 DMRs identified in the established phenotype, 56 were perturbed already at birth and linked, at least in part, to prenatal influences such as tobacco smoke exposure or phthalate exposure.This is the first epigenetic study based on whole genome sequencing to identify marked dysregulation of enhancer regions as a hallmark of childhood asthma.
Evaluation of All-Cause and Cause-Specific Mortality by Race and Ethnicity Among Pregnant and Recently Pregnant Women in the US, 2019 to 2020
Authors: Jeffrey T. Howard, Jessica K. Perrotte, Caleb Leong, Timothy J. Grigsby, Krista J. Howard
Journal: JAMA Network Open (2023)

This cross-sectional study examines all-cause and cause-specific mortality rates among pregnant and recently pregnant US women from 2019 to 2020 and compares mortality rates by race and ethnicity.
Peer Review in a General Medical Research Journal Before and During the COVID-19 Pandemic
Authors: Roy H. Perlis, Jacob Kendall-Taylor, Kamber Hart, Ishani Ganguli, Jesse A. Berlin, Steven M. Bradley, Sebastien Haneuse, Sharon K. Inouye, Elizabeth A. Jacobs, Arden Morris, Olugbenga Ogedegbe, Eli Perencevich, Lawrence N. Shulman, N. Seth Trueger, Stephan D. Fihn, Frederick P. Rivara, Annette Flanagin
Journal: JAMA Network Open (2023)

Importance Although peer review is an important component of publication for new research, the viability of this process has been questioned, particularly with the added stressors of the COVID-19 pandemic. Objective To characterize rates of peer reviewer acceptance of invitations to review manuscripts, reviewer turnaround times, and editor-assessed quality of reviews before and after the start of the COVID-19 pandemic at a large, open-access general medical journal. Design, Setting, and Participants This retrospective, pre-post cohort study examined all research manuscripts submitted to JAMA Network Open between January 1, 2019, and June 29, 2021, either directly or via transfer from other JAMA Network journals, for which at least 1 peer review of manuscript content was solicited. Measures were compared between the period before the World Health Organization declaration of a COVID-19 pandemic on March 11, 2020 (14.3 months), and the period during the pandemic (15.6 months) among all reviewed manuscripts and between pandemic-period manuscripts that did or did not address COVID-19. Main Outcomes and Measures For each reviewed manuscript, the number of invitations sent to reviewers, proportions of reviewers accepting invitations, time in days to return reviews, and editor-assessed quality ratings of reviews were determined. Results In total, the journal sought review for 5013 manuscripts, including 4295 Original Investigations (85.7%) and 718 Research Letters (14.3%); 1860 manuscripts were submitted during the prepandemic period and 3153 during the pandemic period. Comparing the prepandemic with the pandemic period, the mean (SD) number of reviews rated as high quality (very good or excellent) per manuscript increased slightly from 1.3 (0.7) to 1.5 (0.7) ( P &amp;amp;lt; .001), and the mean (SD) time for reviewers to return reviews was modestly shorter (from 15.8 [7.6] days to 14.4 [7.0] days; P &amp;amp;lt; .001), a difference that persisted in linear regression models accounting for manuscript type, study design, and whether the manuscript addressed COVID-19. Conclusions and Relevance In this cohort study, the speed and editor-reported quality of peer reviews in an open-access general medical journal improved modestly during the initial year of the pandemic. Additional study will be necessary to understand how the pandemic has affected reviewer burden and fatigue.
A Single Nucleotide Variant in the PPARγ-homolog <i>Eip75B</i> Affects Fecundity in <i>Drosophila</i>
Authors: Katja M Hoedjes, Hristina Kostic, Thomas Flatt, Laurent Keller
Journal: Molecular Biology and Evolution (2023)

Single nucleotide polymorphisms are the most common type of genetic variation, but how these variants contribute to the adaptation of complex phenotypes is largely unknown. Experimental evolution and genome-wide association studies have demonstrated that variation in the PPARγ-homolog Eip75B has associated with longevity and life-history differences in the fruit fly Drosophila melanogaster. Using RNAi knockdown, we first demonstrate that reduced expression of Eip75B in adult flies affects lifespan, egg-laying rate, and egg volume. We then tested the effects of a naturally occurring SNP within a cis-regulatory domain of Eip75B by applying two complementary approaches: a Mendelian randomization approach using lines of the Drosophila Genetic Reference Panel, and allelic replacement using precise CRISPR/Cas9-induced genome editing. Our experiments reveal that this natural polymorphism has a significant pleiotropic effect on fecundity and egg-to-adult viability, but not on longevity or other life-history traits. Our results provide a rare functional validation at the nucleotide level and identify a natural allelic variant affecting fitness and life-history adaptation.
Novel murine glioblastoma models that reflect the immunotherapy resistance profile of a human disease
Authors: Chao-Hsien Chen, Renee L Chin, Genevieve P Hartley, Spencer T Lea, Brian J Engel, Cheng-En Hsieh, Rishika Prasad, Jason Roszik, Takashi Shingu, Gregory A Lizee, Amy B Heimberger, Steven W Millward, Jian Hu, David S Hong, Michael A Curran
Journal: Neuro-Oncology (2023)

Abstract Background The lack of murine glioblastoma models that mimic the immunobiology of human disease has impeded basic and translational immunology research. We, therefore, developed murine glioblastoma stem cell lines derived from Nestin-CreERT2QkL/L; Trp53L/L; PtenL/L (QPP) mice driven by clinically relevant genetic mutations common in human glioblastoma. This study aims to determine the immune sensitivities of these QPP lines in immunocompetent hosts and their underlying mechanisms. Methods The differential responsiveness of QPP lines was assessed in the brain and flank in untreated, anti-PD-1, or anti-CTLA-4 treated mice. The impact of genomic landscape on the responsiveness of each tumor was measured through whole exome sequencing. The immune microenvironments of sensitive (QPP7) versus resistant (QPP8) lines were compared in the brain using flow cytometry. Drivers of flank sensitivity versus brain resistance were also measured for QPP8. Results QPP lines are syngeneic to C57BL/6J mice and demonstrate varied sensitivities to T cell immune checkpoint blockade ranging from curative responses to complete resistance. Infiltrating tumor immune analysis of QPP8 reveals improved T cell fitness and augmented effector-to-suppressor ratios when implanted subcutaneously (sensitive), which are absent on implantation in the brain (resistant). Upregulation of PD-L1 across the myeloid stroma acts to establish this state of immune privilege in the brain. In contrast, QPP7 responds to checkpoint immunotherapy even in the brain likely resulting from its elevated neoantigen burden. Conclusions These syngeneic QPP models of glioblastoma demonstrate clinically relevant profiles of immunotherapeutic sensitivity and potential utility for both mechanistic discovery and evaluation of immune therapies.
Cabozantinib plus durvalumab in advanced gastroesophageal cancer and other gastrointestinal malignancies: Phase Ib CAMILLA trial results
Authors: Anwaar Saeed, Robin Park, Junqiang Dai, Raed Al-Rajabi, Anup Kasi, Joaquina Baranda, Stephen Williamson, Azhar Saeed, Jacob Ripp, Zachary Collins, Kelly Mulvaney, Molly Shugrue, Jeanette Firth-Braun, Andrew K. Godwin, Rashna Madan, Milind Phadnis, Weijing Sun
Journal: Cell Reports Medicine (2023)

This is the phase Ib part of the phase I/II CAMILLA trial evaluating cabozantinib plus durvalumab in advanced chemo-refractory proficient mismatch repair or microsatellite stable (pMMR/MSS) gastrointestinal malignancies including gastric/gastroesophageal junction/esophageal (G/GEJ/E) adenocarcinoma, colorectal cancer (CRC), and hepatocellular carcinoma (HCC). Thirty-five patients are enrolled. There are no observed dose-limiting toxicities during dose escalation. The overall grade 3/4 treatment-related adverse event rate is 34%. Among evaluable patients (n = 30), the objective response rate (ORR) is 30%, disease control rate (DCR) 83.3%, 6-month progression-free survival (PFS) 36.7%, median PFS 4.5 months, and median overall survival (OS) 8.7 months. Responses are seen in 4 of 17, 3 of 10, and 2 of 3 patients with CRC, G/GEJ/E adenocarcinoma, and HCC, respectively. Participants with a PD-L1 combined positive score (CPS) ≥5 have numerically higher ORR, PFS, and OS. Cabozantinib plus durvalumab demonstrates a tolerable safety profile and potential efficacy in previously treated advanced pMMR/MSS gastrointestinal malignancies.
Differences in IgG autoantibody Fab glycosylation across autoimmune diseases
Authors: Jana Koers, Rocco Sciarrillo, Ninotska I.L. Derksen, Esther M. Vletter, Yvonne E. Fillié-Grijpma, Elisabeth Raveling-Eelsing, Nuno A.G. Graça, Thiemo Leijser, Hendri H. Pas, L. Laura van Nijen-Vos, Maaike V.J. Braham, Anne-Marie Buisman, Jan de Jong, Angela I. Schriek, Anne P. Tio-Gillen, Y.K. Onno Teng, Maurice Steenhuis, Francis H. Swaneveld, Steven W. de Taeye, Marit J. van Gils, Jan J.G.M. Verschuuren, Bram Rutgers, Peter Heeringa, Barbara Horváth, Bart C. Jacobs, Karina de Leeuw, Casper F.M. Franssen, Agnès Veyradier, Paul Coppo, Kyra A. Gelderman, S. Marieke van Ham, Cécile A.C.M. van Els, Diane van der Woude, Ruth Huizinga, Maartje G. Huijbers, Taco W. Kuijpers, Rene E.M. Toes, Nicolaas A. Bos, Theo Rispens
Journal: Journal of Allergy and Clinical Immunology (2023)
All-in-one bioactive properties of photothermal nanofibers for accelerating diabetic wound healing
Authors: Yanan Zhao, Chuan Tian, Yiming Liu, Zaoqu Liu, Jing Li, Zijian Wang, Xinwei Han
Journal: Biomaterials (2023)

Diabetic wound healing has attracted widespread attention in biomedical engineering. However, the harsh hypoxic microenvironment (HME) comprising high glucose levels, local bleeding, and bacterial infection often leads to the formation of hyperplastic scars, increasing the clinical demand for wound dressings. Here, we report a comprehensive strategy using near-infrared NIR-assisted oxygen delivery combined with the bioactive nature of biopolymers for remodeling the HME. Black phosphorus (BP) nanosheets and hemoglobin (Hb) were self-assembled layerwise onto electrospun poly-l-lactide (PLLA) nanofibers using charged quaternized chitosan (QCS) and hyaluronic acid. BP converts NIR radiation into heat and stimulates Hb to release oxygen in situ. QCS is a hemostatic and broad-spectrum antibacterial material. Moderate BP-derived photothermal therapy can increase the sensitivity of bacteria to QCS. A series of composite wound dressings (coded as PQBH-n) with different numbers of layers were fabricated, and the in vivo diabetic wound healing potentials were tested. The molecular mechanism can be partly attributed to the cytokine-cytokine receptor interaction. Notably, this comprehensive strategy based on NIR-assisted oxygen delivery combined with the bioactive properties of biopolymers is not only applicable for fabricating multifunctional wound dressings but also has a great potential in expanding biomedical engineering fields.
When I use a word . . . . The Lelamour Herbal
Authors: Jeffrey K Aronson
Journal: BMJ (2023)

In 1373 John Lelamour, a Hereford schoolmaster, compiled the text of what became known as the Lelamour Herbal. It describes the therapeutic properties of more than 200 plant species. The date of the manuscript is given in the explicit to the text, as is its supposed source, a translation of <i>De viribus herbarum</i>, a popular Latin poem in hexameters composed by “Macer Floridus,” a pseudonym for a French physician from Meung-sur-Loire, Odo Magdunensis. However, textual, linguistic, graphological, and other evidence suggests that Macer’s poem contributed only some of the material for the Herbal, which relied on several other sources and may not have dated solely from a compilation in 1373. The Lelamour Herbal is cited 132 times in the <i>Oxford English Dictionary</i>, and in many cases the words referred to in the citations illustrate the first recorded instances of their meanings, assuming a true date of compilation of 1373. Even if that assumption is wrong, the text is clearly important from a lexicographic point of view.
Colonization by ceftazidime/avibactam-resistant KPC-producing Klebsiella pneumoniae following therapy in critically ill patients
Authors: Paolo Gaibani, Federica Bovo, Linda Bussini, Michele Bartoletti, Tiziana Lazzarotto, Pierluigi Viale, Federico Pea, Simone Ambretti
Journal: Clinical Microbiology and Infection (2023)
Treatment Outcomes of Older Participants in a Randomized Trial Comparing Two Schedules of Twice-Daily Thoracic Radiotherapy in Limited-Stage SCLC
Authors: Kristin Toftaker Killingberg, Bjørn Henning Grønberg, Marit Slaaen, Øyvind Kirkevold, Tarje Onsøien Halvorsen
Journal: Journal of Thoracic Oncology (2023)

Half of the patients with limited-stage SCLC (LS SCLC) are above or equal to 70 years old, but they account for less than 20% of participants in most trials. Comorbidities and reduced organ and physical function might lead to more treatment toxicity, and population-based studies indicate that fewer older than younger patients with LS SCLC receive standard chemoradiotherapy, although there is limited evidence for such a policy.We compared baseline characteristics, comorbidity, survival, treatment completion, toxicity, health-related quality of life, and treatment outcomes between patients above or equal to 70 years old and those younger than 70 years old in an open-label, randomized phase II trial comparing twice-daily thoracic radiotherapy of 45 Gy in 30 fractions with 60 Gy in 40 fractions in LS SCLC. All patients received concurrent i.v. cisplatin (75mg/m2) or carboplatin (AUC 5-6 mg/ml x min) day 1 and i.v. etoposide (100 mg/m2) day 1-3 chemotherapy. This trial is registered at ClinicalTrials.gov (NCT02041845).A total of 170 patients who were above or equal to 18 years old and had performance status of 0 to 2 were randomized. Of these, 53 patients (60 Gy: 25, 45 Gy: 28) were above or equal to 70 years old and 117 (60 Gy: 64, 45 Gy: 53) were younger. There were no differences in baseline characteristics, treatment completion rates, toxicity, or response rates across the age groups. Health-related quality of life mean scores were similar during year one, but older patients reported more decline on functional scales than younger patients during year two. Overall survival was shorter for older patients, whereas there was no difference in progression-free survival or time to progression.Patients above or equal to 70 years old tolerated concurrent twice-daily chemoradiotherapy and achieved similar disease control as younger patients, indicating older patients should receive the same treatment as younger patients.
Inhibition of VEGF-B signaling prevents non-alcoholic fatty liver disease development by targeting lipolysis in the white adipose tissue
Authors: Annelie Falkevall, Annika Mehlem, Erika Folestad, Frank Chenfei Ning, Óscar Osorio-Conles, Rosa Radmann, Ana de Hollanda, Samuel D. Wright, Pierre Scotney, Andrew Nash, Ulf Eriksson
Journal: Journal of Hepatology (2023)

Hepatic steatosis is a hallmark of non-alcoholic fatty liver disease (NAFLD), a common comorbidity in type 2 diabetes mellitus (T2DM). The pathogenesis of NAFLD is complex and involves the crosstalk between the liver and the white adipose tissue (WAT). Vascular endothelial growth factor B (VEGF-B) has been shown to control tissue lipid accumulation by regulating the transport properties of the vasculature. The role of VEGF-B signaling and the contribution to hepatic steatosis and NAFLD in T2DM is currently not understood.C57BL/6 J mice treated with a neutralizing antibody against VEGF-B, or mice with adipocyte-specific overexpression or under-expression of VEGF-B (AdipoqCre+/VEGF-BTG/+ mice and AdipoqCre+/Vegfbfl/+mice) were subjected to a 6-month high-fat diet (HFD), or chow-diet, whereafter NAFLD development was assessed. VEGF-B expression was analysed in WAT biopsies from patients with obesity and NAFLD in a pre-existing clinical cohort (n = 24 patients with NAFLD and n = 24 without NAFLD) and correlated to clinicopathological features.Pharmacological inhibition of VEGF-B signaling in diabetic mice reduced hepatic steatosis and NAFLD by blocking WAT lipolysis. Mechanistically we show, by using HFD-fed AdipoqCre+/VEGF-BTG/+ mice and HFD-fed AdipoqCre+/Vegfbfl/+mice, that inhibition of VEGF-B signaling targets lipolysis in adipocytes. Reducing VEGF-B signaling ameliorated NAFLD by decreasing WAT inflammation, resolving WAT insulin resistance, and lowering the activity of the hormone sensitive lipase. Analyses of human WAT biopsies from individuals with NAFLD provided evidence supporting the contribution of VEGF-B signaling to NAFLD development. VEGF-B expression levels in adipocytes from two WAT depots correlated with development of dysfunctional WAT and NAFLD in humans.Taken together, our data from mouse models and humans suggest that VEGF-B antagonism may represent an approach to combat NAFLD by targeting hepatic steatosis through suppression of lipolysis.Non-alcoholic fatty liver disease (NAFLD) is a common comorbidity in type 2 diabetes mellitus (T2DM) and has a global prevalence of between 25-29%. There are currently no approved drugs for NAFLD, and given the scale of the ongoing diabetes epidemics, there is an urgent need to identify new treatment options. Our work suggests that VEGF-B antagonism may represent an approach to combat NAFLD by targeting hepatic steatosis through suppression of lipolysis. The neutralizing anti-VEGF-B antibody, which was used in this study, has already entered clinical trials for patients with diabetes. Therefore, we believe that our results are of great general interest to a broad audience, including patients and patient organizations, the medical community, academia, the life science industry and the public.